Synthesis of carbamoylpyridone hiv integrase inhibitors and intermediates

ABSTRACT

A synthesis approach providing an early ring attachment via a bromination to compound l-l yielding compound II-Il, whereby a final product such as AA can be synthesized. In particular, the 2,4-difluorophenyl-containing sidechain is attached before creation of the additional ring Q.

FIELD OF THE INVENTION

The present invention comprises modifications of known processes forsynthesizing compounds having HIV integrase inhibitory activity.

BACKGROUND OF THE INVENTION

WO 2006/116764 published 2 Nov. 2006, incorporated by reference in itsentirety, describes various compounds and detailed synthetic schemes fortheir preparation. In particular, a reaction sequence is depicted atpage 79 thereof wherein 3-benzyloxy-2-methyl-1H-pyridine-4-one offormula 3 is there brominated to the bromopyridine 4 there, which isthen reacted with methanol and carbon monoxide to yield the nicotinicacid methyl ester 5 there which is after several steps reacted with abenzylamine to create the amide side chain-containing pyridine 10. Thus,the amide sidechain is in place before creation of the Z¹Z² ring of thefinal product formula (I) therein in the reaction depicted at page 80from 16 to 17-1.

A second reaction sequence is depicted at page 113 of WO 2006/116764wherein a pyrrolidine compound 102 is allowed to condense into atricyclic compound 103 which is then brominated to yield the brominecompound 104 which is then reacted with a benzylamine to create theamide side chain-containing tricyclic compound 105 therein. Thus, thebromination takes place after creation of the Z¹Z² ring of the finalproduct of formula (I) therein.

N-Methoxy-N-methyl amides may be prepared by Pd catalyzedaminocarbonylation of aryl bromides as described by J. R. Martinelli etal in Organic Letters, Vol. 8, No. 21, pages 4843-4846 (2006).Bromoanilines and bromoanisoles are converted to esters as described byJ. Albaneze-Walker et al in Organic Letters, Vol. 6, No. 13, pages2097-2100 (2004).

SUMMARY OF THE INVENTION

Processes are provided which utilize an early bromination step in theconstruction of compounds useful as having HIV integrase inhibitoryactivity as set forth in WO 2006/116764. The bromination provides theleaving group for attachment of an amide side chain on a pyridone ring.

DETAILED DESCRIPTION OF THE INVENTION

A process is provided within a synthesis of a pyridone compound of thefollowing formula (AA), (BB) or (CC):

comprising the steps of:

-   -   P-1) brominating a compound of the following formula (I-I) to        produce a bromine compound of the following formula (II-II):

-   -   wherein        -   R is —CHO, —CH(OH)₂, —CH(OH)(OR⁴), —CH(OH)—CH₂OH or            —CH(OR⁵)(OR⁶);        -   P¹ is H or a hydroxyl protecting group;        -   P³ is H or a carboxy protecting group;        -   R⁴ is lower alkyl;        -   R⁵ and R⁶ are independently lower alkyl or R⁵ and R⁶ can be            lower alkyl and joined to form a 5-, 6-, or 7-membered ring,            and    -   P-2) creating the 2,4-di-fluorophenyl-CH₂—NH—C(O)— sidechain        with the reactants 2,4-di-fluorophenyl-CH₂—NH₂ and carbon        monoxide.

The term “lower alkyl”, alone or in combination with any other term,refers to a straight-chain or branched-chain saturated aliphatichydrocarbon radical containing 1 to 6 carbon atoms. Examples of alkylradicals include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl,n-hexyl and the like.

The term “lower cycloalkyl” refers to a saturated or partially saturatedcarbocyclic ring composed of 3-6 carbons in any chemically stableconfiguration. Examples of suitable carbocyclic groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohexenyl.

The term “lower alkenyl,” alone or in combination with any other term,refers to a straight-chain or branched-chain alkyl group with one or twocarbon-carbon double bonds. Examples of alkenyl radicals include, butare not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl,pentenyl, hexenyl, hexadienyl and the like.

The term “lower alkylene” refers to a straight or branched chaindivalent hydrocarbon radical, preferably having from one to six carbonatoms, unless otherwise defined. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, propylene,butylene, isobutylene and the like.

The term “lower alkenylene” refers to a straight or branched chaindivalent hydrocarbon radical, one or two carbon-carbon double bonds.

The term “lower alkoxy” refers to an alkyl ether radical, wherein theterm “alkyl” is defined above. Examples of suitable alkyl ether radicalsinclude, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

The term “halogen” refers fluorine (F), chlorine (CI), bromine (Br), oriodine (I).

The term “aryl” alone or in combination with any other term, refers to acarbocyclic aromatic moiety (such as phenyl or naphthyl) containing 6carbon atoms, and more preferably from 6-10 carbon atoms. Examples ofaryl radicals include, but are not limited to, phenyl, naphthyl,indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl,tetrahydronaphthyl, indanyl, phenanthridinyl and the like. Unlessotherwise indicated, the term “aryl” also includes each possiblepositional isomer of an aromatic hydrocarbon radical, such as in1-naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl,1-phenanthridinyl, 2-phenanthridinyl, 3-phenanthridinyl,4-phenanthridinyl, 7-phenanthridinyl, 8-phenanthridinyl,9-phenanthridinyl and 10-phenanthridinyl. Examples of aryl radicalsinclude, but are not limited to, phenyl, naphthyl, indenyl, azulenyl,fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl,phenanthridinyl and the like. The term “aralkyl” refers to an alkylgroup substituted by an aryl. Examples of aralkyl groups include, butare not limited to, benzyl and phenethyl.

The term “heterocyclic group,” and “heterocycle” as used herein, referto a 3- to 7-membered monocyclic heterocyclic ring or 8- to 11-memberedbicyclic heterocyclic ring system any ring of which is either saturated,partially saturated or unsaturated, and which may be optionallybenzofused if monocyclic. Each heterocycle consists of one or morecarbon atoms and from one to four heteroatoms selected from the groupconsisting of N, O and S, and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen atom mayoptionally be quaternized, and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached at any carbon or heteroatom, providedthat the attachment results in the creation of a stable structure.Preferred heterocycles include 5-7 membered monocyclic heterocycles and8-10 membered bicyclic heterocycles. When the heterocyclic ring hassubstituents, it is understood that the substituents may be attached toany atom in the ring, whether a heteroatom or a carbon atom, providedthat a stable chemical structure results. “Heteroaromatics” or“heteroaryl” are included within the heterocycles as defined above andgenerally refers to a heterocycle in which the ring system is anaromatic monocyclic or polycyclic ring radical containing five to twentycarbon atoms, preferably five to ten carbon atoms, in which one or morering carbons, preferably one to four, are each replaced by a heteroatomsuch as N, O, S and P. Preferred heteroaryl groups include 5-6 memberedmonocyclic heteroaryls and 8-10 membered bicyclic heteroaryls. Alsoincluded within the scope of the term “heterocycle, “heterocyclic” or“heterocyclyl” is a group in which a non-aromatic heteroatom-containingring is fused to one or more aromatic rings, such as in an indolinyl,chromanyl, phenanthridinyl or tetrahydro-quinolinyl, where the radicalor point of attachment is on the non-aromatic heteroatom-containingring. Unless otherwise indicated, the term “heterocycle, “heterocyclic”or “heterocyclyl” also included each possible positional isomer of aheterocyclic radical, such as in 1-indolinyl, 2-indolinyl, 3-indolinyl.Examples of heterocycles include imidazolyl, imidazolinoyl,imidazolidinyl, quinolyl, isoquinolyl, indolyl, indazolyl,indazolinolyl, perhydropyridazyl, pyridazyl; pyridyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazinyl, quinoxolyl, piperidinyl,pyranyl, pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl,morpholinyl, thiamorpholinyl, furyl, thienyl, triazolyl, thiazolyl,carbolinyl, tetrazolyl, thiazolidinyl, benzofuranoyl, thiamorpholinylsulfone, oxazolyl, oxadiazolyl, benzoxazolyl, oxopiperidinyl,oxopyrrolidinyl, oxoazepinyl, azepinyl, isoxozolyl, isothiazolyl,furazanyl, tetrahydropyranyl, tetrahydrofuranyl, thiazolyl, thiadiazoyl,dioxolyl, dioxinyl, oxathiolyl, benzodioxolyl, dithiolyl, thiophenyl,tetrahydrothiophenyl, sulfolanyl, dioxanyl, dioxolanyl,tetahydrofurodihydrofuranyl, tetrahydropyranodihydrofuranyl,dihydropyranyl, tetradyrofurofuranyl and tetrahydropyranofuranyl.

Optional substituents are hydroxy, halogen, amino and lower alkyl:

Protecting groups may be selected from groups known to those skilled inthe art, including protecting groups disclosed in Greene, Theodora W.;Wuts, Peter G. M. Protective Groups in Organic Synthesis. 2nd Ed.(1991), 473 pp. or Kocienski, Philip J. Protecting Groups. 3rd Ed. 2005,(2005), 679 pp.

The pyridone ring depicted in (I-I) and (II-II), ie to which the —OP¹ isdirectly attached, becomes in AA, BB and CC the ring shown next to the Qring as follows:

Thus, the step P-2) can be carried out before or after creation of the Qring, such steps for the creation of the Q ring being described hereinand in WO 2006/1116764.

The present invention features a process as described above, whereinsaid step P-2) is carried out before creation of the Q ring and whereinsaid pyridone compound is of the formula AA or formula BB or formula CC.

The present invention features a process as described above, whereinsaid step P-2) is carried out after creation of the Q ring and whereinsaid pyridone compound is of the formula AA or formula BB or formula CC.

The present invention features a process as described above, wherein thepyridone compound is of the formula AA.

The present invention features a process as described above, wherein thepyridone compound is of the formula BB.

The present invention features a process as described above, wherein thepyridone compound is of the formula CC.

Also part of the present invention are novel intermediates such as thoseof the following formula (DD) below:

wherein P¹ is as described above, particularly benzyl.

A process is provided for the preparation of a pyridone compound of thefollowing formula (AA), (BB) or (CC):

comprising the steps of:

-   -   P-1) brominating a compound of the following formula (I-I) to        produce a bromine compound of the following formula (II-II):

-   -   wherein        -   R is —CHO; —CH(OH)₂, —CH(OH)(OR⁴), —CH(OH)—CH₂OH or            —CH(OR⁵)(OR⁶);        -   P¹ is H or a hydroxyl protecting group;        -   P³ is H or a carboxy protecting group;        -   R⁴ is lower alkyl;        -   R⁵ and R⁶ are independently lower alkyl or R⁵ and R⁶ can be            lower alkyl and joined to form a 5-, 6-, or 7-membered ring,    -   P-2) creating the 2,4-di-fluorophenyl-CH₂—NH—C(O)— sidechain        with the reactants 2,4-di-fluorophenyl-CH₂—NH₂ and carbon        monoxide to form a compound of formula

-   -   P-3) condensing and debenzylating a compound of formula III-III        to form a compound of formula AA, BB, or CC.

The present invention also features processes as described above whereinP¹ is benzyl; P³ is methyl; and R is —CHO, —CH(OH)(OR⁴), —CH(OR⁵)(OR⁵)wherein R⁴ and R⁵ are lower alkyl.

There is also described herein the process for the preparation of acompound of the following formula (I):

-   -   wherein        -   R is —CHO, —CH(OH)₂ or —CH(OH)(OR⁴);        -   P¹ is H or a hydroxyl protecting group;        -   P³ is H or a carboxy protecting group;        -   R³ is H, halogen, hydroxy, optionally substituted lower            alkyl, optionally substituted cycloalkyl, optionally            substituted lower alkenyl, optionally substituted lower            alkoxy, optionally substituted lower alkenyloxy, optionally            substituted aryl, optionally substituted aryloxy, optionally            substituted heterocyclic group, optionally substituted            heterocycleoxy and optionally substituted amino;        -   R⁴ is lower alkyl;        -   R^(x) is H, halo or R²—X—NR′—C(O)—;        -   R² is optionally substituted aryl;        -   X is a single bond, a heteroatom group selected from O, S,            SO, SO₂, and NH or loweralkylene or lower alkenylene wherein            each may be intervened by the heteroatom; and        -   R¹ is H or lower alkyl,            which comprises the steps of:    -   i) reacting a compound of formula (II):

-   -   with an amine of formula (III) or (IV):

-   -   wherein R⁵ and R⁶ are independently lower alkyl or R⁵ and R⁶ can        be alkyl and joined to form a 5-, 6-, or 7-membered ring,

to produce an intermediate of formula (V) or (VI), respectively:

-   -   ii) refunctionalizing (V) or (VI) to produce (I).

Specific compounds used in the processes include those of the followingformulae (IIa), (VIa), (VIb) and (Ia) utilized in Examples which follow:

The product (Ia) of a synthetic sequence can be condensed with an amine,eg of the formula H₂NCH₂CH₂CH₂OH, brominated if R^(x) is H, carbonylatedand amidated and finally, debenzylated to yield a compound of WO2006/116764 designated (I-7) at page 240 wherein (R)_(m) is 4-F andR^(a) is H. Alternatively, such a compound may be synthesized bystarting with (I) where R^(x) is p-F-phenyl-CH₂—NH—C(O)—, R³ is H, P¹ isbenzyl (Bn) and P³ is a carboxy protecting group.

In more detail, step i) can be carried out in a protic or aproticsolvent such as EtOH, THF or DMF at a temperature of about 50-150° C.for about 1-10 hours.

In more detail, step ii) can be carried out for the diol startingmaterial (VI) with an oxidizing agent such as NaIO₄, RuO₄ or Pb(OAc)₄ ina solvent such as H₂O, MeOH or CH₃CN at ambient temperature for one ormore hours. For the acetal type starting material such as (V), reactionmay be in an acid such as HCl, CF₃COOH or HCOH optionally with heating.

Step ii) can also involve refunctionalization at the R^(x) position, egR^(x)=H to R^(x)=Br optionally with further refunctionalization toR^(x)=R²—X—NR′—C(O)—. Step ii) can also involve refunctionalization ofP³, eg P³=H to P³=Me.

In more detail, step P-1) can be carried out by treating a compound offormula I-I with a bromine source including but not limited toN-bromosuccinimide or bromine in a solvent such as N,N-dimethylformamide, THF or acetic acid and the like. This transformation can berun particularly at a temperature of −10° C. to 50° C. to produce acompound of formula II-II.

In more detail, step P-2) can be carried out by treating a compound offormula II-II with 2,4-difluorophenyl-CH₂—NH₂, carbon monoxide, asuitable base and palladium (0) source and optionally an appropriateligand in an inert solvent optionally with heating. The carbon monoxidecan be at atmospheric pressure (14.7 psi) or at elevated pressureparticularly in the range of up to 60 psi but in some cases higherpressures may be required. Bases include but are not limited to tertiaryamine bases such as diisopropylethylamine and triethylamine and thelike. Inorganic bases such as potassium acetate and potassium phosphateare also bases of significance. Suitable sources of Pd (0) include butare not limited to tetrakis triphenylphosphine palladium (0). In somecases a Pd (II) precursor can be used to generate Pd (0) in situ.Suitable Pd (II) precursors include but are not limited to Pd(OAc)₂,Pd(OCOCF₃)₂ and ligands include Xantphos, diphenylphosphinoferrocene(dppf), triphenylphosphine and the like. Solvents include N,N-dimethylformamide, THF, toluene, DMSO and the like. Heating the mixture isoptionally used in the range from ambient to 150° C.

The present invention also features crystalline forms of a compound offormula AA (Compound 13, Example 1) salt and a hydrate thereof. Thepresent invention features:

(1) A salt or a hydrate thereof of a compound of formula AA:

(2) A crystal form of a sodium salt or a hydrate thereof of a compoundof formula AA:

(3) A crystal form of (2) having one or more physical propertiesselected from the group consisting of (i) and (ii):

-   (i) having characteristic diffraction peaks at 6.4°±0.2°, 9.2°±0.2°,    13.8°±0.2°, 19.2°±0.2° and 21.8°±0.2° degrees two-theta in an X-ray    powder diffraction pattern; and-   (ii) having characteristic infrared absorption spectra at 1641    cm⁻¹±2 cm⁻¹, 1536 cm⁻¹±2 cm⁻¹, 1503 cm⁻¹±2 cm⁻¹ and 1424 cm⁻¹±2    cm⁻¹.    (4) A crystal form of (2) having characteristic diffraction peaks at    6.4°±0.2°, 9.2°±0.2°, 13.8°±0.2°, 19.2°±0.2° and 21.8°±0.2° degrees    two-theta in an X-ray powder diffraction pattern.    (5) A crystal form of (2) having characteristic diffraction peaks at    6.4°±0.2°, 9.2°±0.2°, 13.8°±0.2°, 14.6°±0.2°, 15.2°±0.2°,    17.6°±0.2°, 19.2°±0.2°, 21.8°±0.2°, 24.1°±0.2° and 28.7°±0.0.2°    degrees two-theta in an X-ray powder diffraction pattern.    (6) A crystal form of (2) having characteristic infrared absorption    spectra at 1641 cm⁻¹±2 cm⁻¹, 1536 cm⁻¹±2 cm⁻¹, 1503 cm⁻¹±2 cm⁻¹ and    1424 cm⁻¹±2 cm⁻¹.    (7) A crystal form of (2) having characteristic infrared absorption    spectra at 1641 cm⁻¹±2 cm⁻¹, 1536 cm⁻¹±2 cm⁻¹, 1503 cm⁻¹±2 cm⁻¹,    1424 cm⁻¹±2 cm⁻¹, 1282 cm⁻¹±2 cm⁻¹, 1258 cm⁻¹±2 cm⁻, 1093 cm⁻¹±2    cm⁻¹ and 1069 cm⁻¹±2 cm⁻.    (8) A crystal form of (2) having one or more spectra selected from    the group consisting of (a) to (c):    (a) X-ray powder diffraction pattern substantially as shown in FIG.    1;    (b) Infrared absorption spectra substantially as shown in FIG. 2;    and    (c) Solid state ¹³C-NMR spectra substantially as shown in FIG. 3.    (9) A crystal form of (2) having one or more physical properties    selected from the group consisting of (iii) and (iv):-   (iii) having characteristic diffraction peaks at 8.0°±0.2°,    9.3°±0.2°, 11.3°±0.2°, 16.0°±0.2°, and 22.8°±0.2° degrees two-theta    in an X-ray powder diffraction pattern; and-   (iv) having characteristic infrared absorption spectra at 1637    cm⁻¹±2 cm⁻¹, 1536 cm⁻¹±2 cm⁻¹, 1501 cm⁻¹±2 cm⁻¹ and 1422 cm⁻¹±2    cm⁻¹.    (10) A crystal form of (2) having characteristic diffraction peaks    at 8.0°±0.2°, 9.3°±0.2°, 11.3°±0.2°, 16.0°±0.2° and 22.8°±0.2°    degrees two-theta in an X-ray powder diffraction pattern.    (11) A crystal form of (2) having characteristic diffraction peaks    at 8.0°±0.2°, 9.3°±0.2°, 11.3°±0.2°, 15.4°±0.2°, 16.0°±0.2°,    18.7°±0.2°, 19.1°±0.2°, 19.8°±0.2°, 22.8°±0.2° and 26.8°±0.2°    degrees two-theta in an X-ray powder diffraction pattern.    (12) A crystal form of (2) having characteristic infrared absorption    spectra at 1637 cm⁻¹±2 cm⁻¹, 1536 cm⁻¹±2 cm⁻¹, 1501 cm⁻¹±2 cm⁻¹ and    1422 cm⁻¹±2 cm⁻¹.    (13) A crystal form of (2) having characteristic infrared absorption    spectra at 1637 cm⁻¹±2 cm⁻¹, 1536 cm⁻¹±2 cm⁻¹, 1501 cm⁻¹±2 cm⁻¹,    1422 cm⁻¹±2 cm⁻¹, 1277 cm⁻¹±2 cm⁻¹, 1258 cm⁻¹±2 cm⁻¹, 1093 cm⁻¹±2    cm⁻¹ and 1069 cm⁻¹±2 cm⁻¹.    (14) A crystal form of (2) having one or more spectra selected from    the group consisting of (d) and (e):    (d) X-ray powder diffraction pattern substantially as shown in FIG.    4; and    (e) Infrared absorption spectra substantially as shown in FIG. 5.    (15) A pharmaceutical composition containing the crystal form as    defined in any one of (2) to (14).    (16) A process for preparation of the crystal forms as defined in    any one of (2) to (14).

The present invention features crystalline forms of a salt of compoundof formula AA, in particular a sodium salt.

The present invention features crystalline forms of a hydrate of a saltof a compound of formula AA, in particular a sodium salt.

This invention also includes a crystal form of a compound of formula AA(Compound 12, Example 1). Details are shown as (17) to (22):

(17) A crystal form of a compound of formula AA:

having one or more physical properties selected from the groupconsisting of (v) and (vi):

-   (v) having characteristic diffraction peaks at 5.4°±0.2°,    10.7°±0.2°, 12.3°±0.2°, 15.2°±0.2°, and 16.4°±0.2° degrees two-theta    in an X-ray powder diffraction pattern; and-   (vi) having characteristic infrared absorption spectra at 1658    cm⁻¹±2 cm⁻¹, 1628 cm⁻¹±2 cm⁻¹, 1540 cm⁻¹±2 cm⁻¹ and 1498 cm⁻¹±2    cm⁻¹.    (18) A crystal form of a compound of formula AA:

having characteristic diffraction peaks at 5.4°±0.2°, 10.7°±0.2°,12.3°±0.2°, 15.2°±0.2° and 16.4°±0.2° degrees two-theta in an X-raypowder diffraction pattern.(19) A crystal form of a compound of formula AA:

having characteristic diffraction peaks at 5.4°±0.2°, 10.7°±0.2°,12.3°±0.2°, 14.3°±0.2°, 15.2°±0.2°, 16.4°±0.2°, 21.7°±0.2°, 24.9°±0.2°,25.4°±0.2° and 27.9°±0.2° degrees two-theta in an X-ray powderdiffraction pattern.(20) A crystal of a compound of formula AA:

having characteristic infrared absorption spectra at 1658 cm⁻¹±2 cm⁻¹,1628 cm⁻¹±2 cm⁻¹, 1540 cm⁻¹±2 cm⁻¹ and 1498 cm⁻¹±2 cm⁻¹.(21) A crystal of a compound of formula AA:

having characteristic infrared absorption spectra at 1658 cm⁻¹±2 cm⁻¹,1628 cm⁻¹±2 cm⁻¹, 1540 cm⁻¹±2 cm⁻¹, 1498 cm⁻¹±2 cm⁻¹, 1355 cm⁻¹±2 cm⁻¹,1264 cm⁻¹±2 cm⁻¹, 1238 cm⁻¹±2 cm⁻¹, 1080 cm⁻¹±2 cm⁻¹ and 1056 cm⁻¹±2cm⁻¹.(22) A crystal of a compound of formula AA:

having one or, more spectra selected from the group consisting of (f)and (g):(f) X-ray powder diffraction pattern substantially as shown in FIG. 6;and(g) Infrared absorption spectra substantially as shown in FIG. 7.

The crystals of compound 13 and 13b (monohydrate form of compound 13)demonstrate high solubility in water or saline, high bioavailability(BA), high maximum drug concentration (Cmax), short maximum drugconcentration time (Tmax), high stability against heat or light, and/orgood handling facility. Therefore, the crystals of compound 13 and 13bare suitable as pharmaceutical ingredients.

In the following examples and throughout this specification, thefollowing abbreviations may be used: Me (methyl), Bn (benzyl), Aq(aqueous), Et (ethyl), C (centrigrade).

EXAMPLES

In the following Examples, those depicting the bromination and amidationreactions of the present invention include Examples C, Example 2 andExample CC.

The following examples are intended for illustration only and are notintended to limit the scope of the invention in any way.

Examples 1 and 3

The starting material of Example 1e and 3e is the compound of formula(IIa) which is also shown as compound 5 below and compound #101 at page113 of WO 2006/116764. The product depicted below as compound 8 is ofthe formula (I). The final product shown below as compound 13 is acompound of formula (I-7) at page 240 of WO 2006/116764 wherein (R), is2,4-di-F and R^(a) is H, provided, however, that there is an alphamethyl at the position designated R¹⁶ in formula (XXVI) at page 65.

Thus, in the above sequence for Example 1, compound 5 is identical tocompound 101 at page 113 of WO 2006/116764 and to formula (IIa) of theprocess of the present invention; compound 6 above is identical toformula (Via) of the process of the present invention; compound 7 aboveis identical to formula (VIb) of the process of the present invention;and compound 8 is identical to formula (Ia) of the process of thepresent invention. Step i) of the invention process is 5 to 6 abovewhile step ii) is 6 to 8.

Example 1a

To a slurry of 2000 g of compound 1(1.0 eq.) in 14.0 L of MeCN wereadded 2848 g of benzyl bromide (1.05 eq.) and 2630 g of K₂CO₃(1.2 eq.).The mixture was stirred at 80° C. for 5 h and cooled to 13° C.Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate wasconcentrated and 3.0 L of THF was added to the residue. The THF solutionwas concentrated to give 3585 g of crude compound 2 as oil. Withoutfurther purification, compound 2 was used in the next step.

¹H NMR (300 MHz, CDCl₃) δ 7.60 (d, J=5.7 Hz, 1H), 7.4-7.3 (m, 5H), 6.37(d, J=5.7 Hz, 1H), 5.17 (s, 2H), 2.09 (s, 3H).

Example 1b

To 904 g of the crude compound 2 was added 5.88 L of THF and thesolution was cooled to −60° C. 5.00 L of 1.0 M of Lithiumbis(trimethylsilylamide) in THF (1.25 eq.) was added dropwise for 2 h tothe solution of compound 2 at −60° C. Then, a solution of 509 g ofbenzaldehyde (1.2 eq.) in 800 mL of THF was added at −60° C. and thereaction mixture was aged at −60° C. for 1 h. The THF solution waspoured into a mixture of 1.21 L of conc.HCl, 8.14 L of ice water and4.52 L of EtOAc at less than 2° C. The organic layer was washed with2.71 L of brine (twice) and the aqueous layer was extracted with 3.98 Lof EtOAc. The combined organic layers were concentrated. To the mixture,1.63 L of toluene was added and concentrated (twice) to provide tolueneslurry of compound 3. Filtration, washing with 0.90 L of cold tolueneand drying afforded 955 g of compound 3 (74% yield from compound 1) as acrystal.

¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, J=5.7 Hz, 1H), 7.5-7.2 (m, 10H), 6.38(d, J=5.7 Hz, 1H), 5.16 (d, J=11.4 Hz, 1H), 5.09 (d, J=11.4 Hz, 1H),4.95 (dd, J=4.8, 9.0 Hz, 1H), 3.01 (dd, J=9.0, 14.1 Hz, 1H), 2.84 (dd,J=4.8, 14.1 Hz, 1H).

Example 1c

To a solution of 882 g of compound 3 (1.0 eq.) in 8.82 L of THF wereadded 416 g of Et₃N (1.5 eq.) and 408 g of methanesulfonyl chloride (1.3eq.) at less than 30° C. After confirmation of disappearance of compound3, 440 mL of NMP and 1167 g of DBU (2.8 eq.) were added to the reactionmixture at less than 30° C. and the reaction mixture was aged for 30min. The mixture was neutralized with 1.76 L of 16% sulfuric acid andthe organic layer was washed with 1.76 L of 2% Na₂SO₃ aq. Afterconcentration of the organic layer, 4.41 L of toluene was added and themixture was concentrated (tree times). After addition of 4.67 L ofhexane, the mixture was cooled with ice bath. Filtration, washing with1.77 L of hexane and drying provided 780 g of compound 4 (94% yield) asa crystal.

¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=5.7 Hz, 1H), 7.50-7.25 (m, 10H),7.22 (d, J=16.2 Hz, 1H), 7.03 (d, J=16.2 Hz, 1H), 6.41 (d, J=5.7 Hz,1H), 5.27 (s, 2H).

Example 1d

To a mixture of 822 g of compound 4 (1.0 eq.) and 11.2 g of RuCl₃.nH₂O(0.02 eq.) in 2.47 L of MeCN, 2.47 L of EtOAc and 2.47 L of H₂O wasadded 2310 g of NaIO₄(4.0 eq.) at less than 25° C. After aging for 1 h,733 g of NaClO₂(3.0 eq.) was added to the mixture at less than 25° C.After aging for 1 h, precipitate was filtered and washed with 8.22 L ofEtOAc. To the filtrate, 1.64 L of 50% Na₂S₂O₃ aq, 822 mL of H₂O and 630mL of conc.HCl were added. The aqueous layer was extracted with 4.11 Lof EtOAc and the organic layers were combined and concentrated. To theresidue, 4 L of toluene was added and the mixture was concentrated andcooled with ice bath. Filtration, washing with 1 L of toluene and dryingprovided 372 g of compound 5 (56% yield) as a crystal.

¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J=5.7 Hz, 1H), 7.54-7.46 (m, 2H),7.40-7.26 (m, 3H), 6.48 (d, J=5.7 Hz, 1H), 5.6 (brs, 1H), 5.31 (s, 2H).

Example 1e

A mixture of 509 g of compound 5 (1.0 eq.) and 407 g of3-amino-propane-1,2-diol (2.5 eq.) in 1.53 L of EtOH was stirred at 65°C. for 1 h and at 80° C. for 6 h. After addition of 18.8 g of3-Amino-propane-1,2-diol (0.1 eq.) in 200 mL of EtOH, the mixture wasstirred at 80° C. for 1 h. After addition of 18.8 g of3-amino-propane-1,2-diol (0.1 eq.) in 200 mL of EtOH, the mixture wasstirred at 80° C. for 30 min. After cooling and addition of 509 mL ofH₂O, the mixture was concentrated. To the residue, 2.54 L of H₂O and2.54 L of AcOEt were added. After separation, the aqueous layer waswashed with 1.02 L of EtOAc. To the aqueous layer, 2.03 L of 12%sulfuric acid was added at less than 12° C. to give crystal of compound6. Filtration, washing with 1.53 L of cold H₂O and drying provided 576 gof compound 6 (83% yield) as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 7.67 (d, J=7.5 Hz, 1H), 7.5-7.2 (m, 5H),6.40 (d, J=7.5 Hz, 1H), 5.07 (s, 2H), 4.2-4.0 (m, 1H), 3.9-3.6 (m, 2H),3.38 (dd, J=4.2, 10.8 Hz, 1H), 3.27 (dd, J=6.0, 10.8 Hz, 1H).

Example 1f

To a slurry of 576 g of compound 6(1.0 eq.: 5.8% of H₂O was contained)in 2.88 L of NMP were added 431 g of NaHCO₃(3.0 eq.) and 160 mL ofmethyl iodide (1.5 eq.) and the mixture was stirred at room temperaturefor 4 h. After cooling to 5° C., 1.71 L of 2N HCl and 1.15 L of 20%NaClaq were added to the mixture at less than 10° C. to give crystal ofcompound 7. Filtration, washing with 1.73 L of H₂O and drying provided507 g of compound 7 (89% yield) as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 7.59 (d, J=7.5 Hz, 1H), 7.40-7.28 (m, 5H),6.28 (d, J=7.5 Hz, 1H), 5.21 (d, J=5.4 Hz, 1H), 5.12 (d, J=10.8 Hz, 1H),5.07 (d, J=10.8 Hz, 1H), 4.83 (t, J=5.7 Hz, 1H), 3.97 (dd, J=2.4, 14.1Hz, 1H), 3.79 (s, 3H), 3.70 (dd, J=9.0, 14.4 Hz, 1H), 3.65-3.50 (m, 1H),3.40-3.28 (m, 1H), 3.26-3.14 (m, 1H).

Example 1 g

To a mixture of 507 g of compound 7(1.0 eq.) in 5.07 L of MeCN, 5.07 Lof H₂O and 9.13 g of AcOH (0.1 eq.) was added 390 g of NaIO₄(1.2 eq.)and the mixture was stirred at room temperature for 2 h. After additionof 1.52 L of 10% Na₂S₂O₃ aq., the mixture was concentrated and cooled to10° C. Filtration, washing with H₂O and drying provided 386 g ofcompound 8 (80% yield) as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 7.62 (d, J=7.5 Hz, 1H), 7.42-7.30 (m, 5H),6.33 (d, J=6.0 Hz, 2H), 6.29 (d, J=7.5 Hz, 1H), 5.08 (s, 2H), 4.95-4.85(m, 1H), 3.80 (s, 3H), 3.74 (d, J=5.1 Hz, 2H).

Example 1 h

After dissolution of a mixture of 378 g of compound 8 (1.0 eq.) in 3.78L of MeOH by heating, the solution was concentrated. To the residue,1.51 L of toluene was added and the mixture was concentrated. To theresidue, 1.89 L of toluene, 378 mL of AcOH and 137 g of(R)-3-Amino-butan-1-ol (1.3 eq.) were added and the mixture was heatedto 90° C., stirred at 90° C. for 2.5 h and concentrated. To the residue,1.89 L of toluene was added and the mixture was concentrated. Theresidue was extracted with 3.78 L and 1.89 L of CHCl₃ and washed with2×1.89 L of H₂O. The organic layers were combined and concentrated. Tothe residue, 1.89 L of EtOAc was added and the mixture was concentrated.After addition of 1.89 L of EtOAc, filtration, washing with 1.13 L ofEtOAc and drying provided 335 g of compound 9 (83% yield) as a crystal.

¹H NMR (300 MHz, CDCl₃) δ 7.70-7.58 (m, 2H), 7.40-7.24 (m, 3H), 7.14 (d,J=7.5 Hz, 2H), 6.47 (d, J=7.5 Hz, 1H), 5.35 (d, J=10.2 Hz, 1H), 5.28 (d,J=10.2 Hz, 1H), 5.12 (dd, J=3.9, 6.3 Hz, 1H), 5.05-4.90 (m, 1H), 4.07(dd, J=3.9, 13.5 Hz, 1H), 4.00-3.86 (m, 3H), 2.23-2.06 (m, 1H), 1.48(ddd, J=2.4, 4.5, 13.8 Hz, 1H), 1.30 (d, J=6.9 Hz, 3H).

Example 1i

To a slurry of 332 g of compound 9 (1.0 eq.) in 1.66 L of NMP was added191 g of NBS (1.1 eq.) and the mixture was stirred at room temperaturefor 2 h. After addition of 1.26 L of H₂O, the mixture was stirred for 30min. After addition of 5.38 L of H₂O and aging of the mixture at 10° C.for 30 min and at 5° C. for 1 h, filtration, washing with 1.33 L of coldH₂O and drying provided 362 g of compound 10 (89% yield) as a crystal.

¹H NMR (300 MHz, CDCl₃) δ 7.69-7.63 (m, 2H), 7.59 (s, 1H), 7.38-7.24 (m,3H), 5.33 (d, J=10.2 Hz, 1H), 5.25 (d, J=9.9 Hz, 1H), 5.12 (dd, J=3.9,5.7 Hz, 1H), 5.05-4.90 (m, 1H), 4.11 (dd, J=3.9, 13.2 Hz, 1H), 4.02-3.88(m, 3H), 2.21-2.06 (m, 1H), 1.49 (ddd, J=2.4, 4.5, 14.1 Hz, 1H), 1.31(d, J=6.9 Hz, 3H).

Example 1j

Under carbon mono-oxide atmosphere, a mixture of 33.5 g of compound 10(1.0 eq.), 34.8 mL of i-Pr₂NEt (2.5 eq.), 14.3 mL of2,4-difluorobenzylamine (1.5 eq.) and 4.62 g of Pd(PPh₃)₄ (0.05 eq.) in335 mL of DMSO was stirred at 90° C. for 5.5 h. After cooling,precipitate was filtered and washed with 50 mL of 2-propanol. Afteraddition of 502 mL of H₂O and 670 mL of AcOEt to the filtrate, theorganic layer was washed with 335 mL of 0.5N HClaq. and 335 mL of H₂Oand the aqueous layer was extracted with 335 mL of AcOEt. The organiclayers were combined and concentrated. To the residue, 150 mL of2-propanol was added and the mixture was concentrated. After addition of150 mL of 2-propanol, concentration, cooling to 20° C. and filtration,crude crystal of compound 11 was obtained. After dissolution of thecrude crystal in 380 mL of acetone by heating, precipitate was filteredand the filtrate was concentrated. After addition of 200 mL of EtOH,concentration, addition of 150 mL of EtOH, concentration, cooling andfiltration, crude crystal of compound 11 was obtained. After dissolutionof the crude crystal in 450 mL of acetone by heating, the solution wasconcentrated. To the residue, 150 mL of 2-propanol was added and themixture was concentrated (twice). After cooling of the residue,filtration, washing with 2-propanol and drying provided 34.3 g ofcompound 11 (84% yield) as a crystal.

¹H NMR (300 MHz, CDCl₃) δ 10.40 (t, J=6.0 Hz, 1H), 8.35 (s, 1H),7.66-7.58 (m, 2H), 7.42-7.24 (m, 5H), 6.78-6.74 (m, 2H), 5.30 (d, J=9.9Hz, 1H), 5.26 (d, J=10.2 Hz, 1H), 5.15 (dd, J=3.9, 5.7 Hz, 1H),5.05-4.90 (m, 1H), 4.64 (d, J=5.4 Hz, 2H), 4.22 (dd, J=3.9, 13.5, 1 H),4.09 (dd, J=6.0, 13.2 Hz, 1H), 4.02-3.88 (m, 2H), 2.24-1.86 (m, 1H),1.50 (ddd, J=2.4, 4.5, 14.1 Hz, 1H), 1.33 (d, J=7.2 Hz, 3H).

Example 1k

Under hydrogen atmosphere, a mixture of 28.0 g of compound 11 (1.0 eq.)and 5.6 g of 10% Pd—C in 252 mL of THF and 28 mL of MeOH was stirred for1 h. After precipitate (Pd—C) was filtered and washed with 45 mL of THF,5.6 g of 10% Pd—C was added and the mixture was stirred for 1.5 h underhydrogen atmosphere. After Pd—C was filtered and washed with 150 mL ofCHCl₃/MeOH (9/1), the filtrate was concentrated. After dissolution ofthe residue in 1.38 L of EtOH by heating, the solution was graduallycooled to room temperature. After filtration, the filtrate wasconcentrated and cooled. Filtration, washing with EtOH and dryingprovided 21.2 g of compound 12 (92% yield) as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 12.51 (s, 1H), 10.36 (t, J=5.7 Hz, 1H), 8.50(s, 1H), 7.39 (td, J=8.7, 6.3 Hz, 1H), 7.24 (ddd, J=2.6, 9.5, 10.8 Hz,1H), 7.12-7.00 (m, 1H), 5.44 (dd, J=3.9, 5.7 Hz, 1H), 4.90-4.70 (m, 1H),4.65-4.50 (m, 1H), 4.54 (d, J=5.1 Hz, 2H), 4.35 (dd, J=6.0, 13.8 Hz,1H), 4.10-3.98 (m, 1H), 3.96-3.86 (m, 1H), 2.10-1.94 (m, 1H), 1.60-1.48(m, 1H), 1.33 (d, J=6.9 Hz, 3H).

Example 1l

After dissolution of 18.0 g of compound 12 (1.0 eq.) in 54 mL of EtOH byheating, followed by filtration, 21.5 mL of 2N NaOHaq. (1.0 eq.) wasadded to the solution at 80° C. The solution was gradually cooled toroom temperature. Filtration, washing with 80 mL of EtOH and dryingprovided. 18.8 g of compound 13 (99% yield) as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (t, J=6.0 Hz, 1H), 7.89 (s, 1H),7.40-7.30 (m, 1H), 7.25-7.16 (m, 1H), 7.06-6.98 (m, 1H), 5.22-5.12 (m,1H), 4.87-4.74 (m, 1H), 4.51 (d, J=5.4 Hz, 2H), 4.35-4.25 (m, 1H), 4.16(dd, J=1.8, 14.1 Hz, 1H), 4.05-3.90 (m, 1H), 3.86-3.74 (m, 1H),2.00-1.72 (m, 1H), 1.44-1.32 (m, 1H), 1.24 (d, J=6.9 Hz, 3H).

Example 1m

Example 1m shows a process for preparation of the crystalline compound13b which is monohydrate form of compound 13.

After dissolution of 30.0 g of compound 13 (1.0 eq.) in 600 mL ofTHF-water solution (8:2) by 30° C., 36.0 mL of 2N NaOHaq (1.0 eq.) wasadded to the solution. The mixture was stirred at room temperature for 2hours. The precipitation was filtered, washing with 150 mL ofTI-IF-water solution (8:2), 150 mL of THF. Drying at 85° C. and humidityconditioning provided 30.4 g of compound 13b (monohydrate form ofcompound 13, 93% yield) as a crystal.

Example 3 Example 3a

To a slurry of 2000 g of compound 1 (1.0 eq.) in 14.0 L of MeCN wereadded 2848 g of benzyl bromide (1.05 eq.) and 2630 g of K₂CO₃ (1.2 eq.).The mixture was stirred at 80° C. for 5 h and cooled to 13° C.Precipitate was filtered and washed with 5.0 L of MeCN. The filtrate wasconcentrated and 3.0 L of THF was added to the residue. The THF solutionwas concentrated to give 3585 g of crude compound 2 as oil. Withoutfurther purification, compound 2 was used in the next step.

¹H NMR (300 MHz, CDCl₃) δ 7.60 (d, J=5.7 Hz, 1H), 7.4-7.3 (m, 5H), 6.37(d, J=5.7 Hz, 1H), 5.17 (s, 2H), 2.09 (s, 3H).

Example 3b

To 904 g of the crude compound 2 was added 5.88 L of THF and thesolution was cooled to −60° C. 5.00 L of 1.0 M of Lithiumbis(trimethylsilylamide) in THF (1.25 eq.) was added dropwise for 2 h tothe solution of compound 2 at −60° C. Then, a solution of 509 g ofbenzaldehyde (1.2 eq.) in 800 mL of THF was added at −60° C. and thereaction mixture was aged at −60° C. for 1 h. The THF solution waspoured into a mixture of 1.21 L of conc.HCl, 8.14 L of ice water and4.52 L of EtOAc at less than 2° C. The organic layer was washed with2.71 L of brine (twice) and the aqueous layer was extracted with 3.98 Lof EtOAc. The combined organic layers were concentrated. To the mixture,1.63 L of toluene was added and concentrated (twice) to provide tolueneslurry of compound 3. Filtration, washing with 0.90 L of cold tolueneand drying afforded 955 g of compound 3 (74% yield from compound 1) as acrystal.

¹H NMR (300 MHz, CDCl₃) δ 7.62 (d, J=5.7 Hz, 1H), 7.5-7.2 (m, 10H), 6.38(d, J=5.7 Hz, 1H), 5.16 (d, J=11.4 Hz, 1H), 5.09 (d, J=11.4 Hz, 1H),4.95 (dd, J=4.8, 9.0 Hz, 1H), 3.01 (dd, J=9.0, 14.1 Hz, 1H), 2.84 (dd,J=4.8, 14.1 Hz, 1H).

Example 3c

To a solution of 882 g of compound 3 (1.0 eq.) in 8.82 L of THF wereadded 416 g of Et₃N (1.5 eq.) and 408 g of methanesulfonyl chloride (1.3eq.) at less than 30° C. After confirmation of disappearance of compound3, 440 mL of NMP and 1167 g of DBU (2.8 eq.) were added to the reactionmixture at less than 30° C. and the reaction mixture was aged for 30min. The mixture was neutralized with 1.76 L of 16% sulfuric acid andthe organic layer was washed with 1.76 L of 2% Na₂SO₃ aq. Afterconcentration of the organic layer, 4.41 L of toluene was added and themixture was concentrated (tree times). After addition of 4.67 L ofhexane, the mixture was cooled with ice bath. Filtration, washing with1.77 L of hexane and drying provided 780 g of compound 4 (94% yield) asa crystal.

¹H NMR (300 MHz, CDCl₃) δ 7.69 (d, J=5.7 Hz, 1H), 7.50-7.25 (m, 10H),7.22 (d, J=16.2 Hz, 1H), 7.03 (d, J=16.2 Hz, 1H), 6.41 (d, J=5.7 Hz,1H), 5.27 (s, 2H).

Example 3d

To a mixture of 10.0 g of compound 4 and 13.6 mg of RuCl₃.nH₂O in 95 mLof MeCN and 10 mL of water, mixture of 155 mL of water, 7.2 g ofhydrosulfuric acid, and 15.5 g of NaIO₄ was added for 2.5 h at 20° C.After aging for 1 h, organic and aqueous layers were separated andaqueous layer was extracted by 30 mL of ethyl acetate. Aqueous layer wasextracted again by 30 mL of ethyl acetate and organic layers werecombined. 6 mL of 5% NaHSO3 solution was added to the combined organiclayer and the layers were separated. The organic layer was adjusted topH 6.0 by adding 4.0 g of 2M NaOH solution and the aqueous layer wasseparated. After 60 mL of 5% NaHCO₃ solution and 257 mg of TEMPO wasadded, 25.9 g of NaClO solution was added to the reaction mixture at 25°C. for 1 h and stirred for 30 min to check the reaction was finished.After the layers were separated, 42.5 mL of 5% Na2SO3 solution and 30 mLof AcOEt were added and separated. The aqueous layer was extracted by 30mL of AcOEt and separated. 12% H₂SO₄ was added to the reaction mixtureat 20° C. for 1 h and the mixture was cooled to 5° C. After the mixturewas stirred for 30 min, the mixture was filtered, washed with 30 mL ofwater twice and dried to provide 5.7 g of compound 5 (70% yield) as acrystal.

¹H NMR (300 MHz, CDCl₃) δ 7.78 (d, J=5.7 Hz, 1H), 7.54-7.46 (m, 2H),7.40-7.26 (m, 3H), 6.48 (d, J=5.7 Hz, 1H), 5.6 (brs, 1H), 5.31 (s, 2H).

Example 3e

A mixture of 509 g of compound 5 (1.0 eq.) and 407 g of3-amino-propane-1,2-diol (2.5 eq.) in 1.53 L of EtOH was stirred at 65°C. for 1 h and at 80° C. for 6 h. After addition of 18.8 g of3-Amino-propane-1,2-diol (0.1 eq.) in 200 mL of EtOH, the mixture wasstirred at 80° C. for 1 h. After addition of 18.8 g of3-amino-propane-1,2-diol (0.1 eq.) in 200 mL of EtOH, the mixture wasstirred at 80° C. for 30 min. After cooling and addition of 509 mL ofH₂O, the mixture was concentrated. To the residue, 2.54 L of H₂O and2.54 L of AcOEt were added. After separation, the aqueous layer waswashed with 1.02 L of EtOAc. To the aqueous layer, 2.03 L of 12%sulfuric acid was added at less than 12° C. to give crystal of compound6. Filtration, washing with 1.53 L of cold H₂O and drying provided 576 gof compound 6 (83% yield) as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 7.67 (d, J=7.5 Hz, 1H), 7.5-7.2 (m, 5H),6.40 (d, J 7.5 Hz, 1H), 5.07 (s, 2H), 4.2-4.0 (m, 1H), 3.9-3.6 (m, 2H),3.38 (dd, J=4.2, 10.8 Hz, 1H), 3.27 (dd, J=6.0, 10.8 Hz, 1H).

Example 3f

To a slurry of 576 g of compound 6 (1.0 eq.: 5.8% of H₂O was contained)in 2.88 L of NMP were added 431 g of NaHCO₃(3.0 eq.) and 160 mL ofmethyl iodide (1.5 eq.) and the mixture was stirred at room temperaturefor 4 h. After cooling to 5° C., 1.71 L of 2N HCl and 1.15 L of 20%NaClaq were added to the mixture at less than 10° C. to give crystal ofcompound 7. Filtration, washing with 1.73 L of H₂O and drying provided507 g of compound 7 (89% yield) as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 7.59 (d, J=7.5 Hz, 1H), 7.40-7.28 (m, 5H),6.28 (d, J=7.5 Hz, 1H), 5.21 (d, J=5.4 Hz, 1H), 5.12 (d, J=10.8 Hz, 1H),5.07 (d, J=10.8 Hz, 1H), 4.83 (t, J=5.7 Hz, 1H), 3.97 (dd, J=2.4, 14.1Hz, 1H), 3.79 (s, 3H), 3.70 (dd, J=9.0, 14.4 Hz, 1H), 3.65-3.50 (m, 1H),3.40-3.28 (m, 1H), 3.26-3.14 (m, 1H).

Example 3 g

To a mixture of 15.0 g of compound 7(1.0 eq.) in 70.9 g of MeCN, amixture of 60 mL of H₂O, 2.6 g of H₂SO₄ and 11.5 g of NaIO₄ was added inthe range between 17° C. to 14° C. After the reaction mixture wasstirred for 1 hour, precipitate was filtered. The filterate was added tothe solution of 11.8 g of ascorbic acid sodium salt, 64 g of water and60 mg of H₂SO₄. After the mixture was concentrated, cooling to 5° C.,filtration, washing with H₂O and drying provided 12.9 g of compound 8(90% yield) as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 7.62 (d, J=7.5 Hz, 1H), 7.42-7.30 (m, 5H),6.33 (d, J=6.0 Hz, 2H), 6.29 (d, J=7.5 Hz, 1H), 5.08 (s, 2H), 4.95-4.85(m, 1H), 3.80 (s, 3H), 3.74 (d, J=5.1 Hz, 2H).

Example 3 h

A mixture of 10.0 g of compound 8 and 33.3 g of diglyme were added thesolution of 3.3 g of (R)-3-Amino-butan-1-ol in 4.7 g of diglyme and 1.0g of acetic acid at 60° C. After the reaction mixture was stirred at 95°C. for 9 hours, the reaction mixture was cooled to −5° C. and filtered.The wet crystal was washed and dried to give 8.3 g of compound 9 (78%).XRD data:

¹H NMR (300 MHz, CDCl₃) δ 7.70-7.58 (m, 2H), 7.40-7.24 (m, 3H), 7.14 (d,J=7.5 Hz, 2H), 6.47 (d, J=7.5 Hz, 1H), 5.35 (d, J=10.2 Hz, 1H), 5.28 (d,J=10.2 Hz, 1H), 5.12 (dd, J=3.9, 6.3 Hz, 1H), 5.05-4.90 (m, 1H), 4.07(dd, J=3.9, 13.5 Hz, 1H), 4.00-3.86 (m, 3H), 2.23-2.06 (m, 1H), 1.48(ddd, J=2.4, 4.5, 13.8 Hz, 1H), 1.30 (d, J=6.9 Hz, 3H).

Example 3i

To slurry of 5.7 g of NBS in 26.5 g of dichloromethane was added 10 g ofcompound 9 in 92.8 g of dichloromethane at room temperature. After thereaction mixture was stirred for 6.5 h, the reaction mixture was addedto the solution of 2.0 g Na2SO3 and 40.3 g of water. The organic layerwas washed with diluted NaOH solution and water, dichloromethane wasconcentrated and was displaced by methanol. The mixture was cooled to−5° C. and filtered and the wet crystal was washed and dried to give10.3 g of compound 10 (84%).

¹H NMR (300 MHz, CDCl₃) δ 7.69-7.63 (m, 2H), 7.59 (s, 1H), 7.38-7.24 (m,3H), 5.33 (d, J=10.2 Hz, 1H), 5.25 (d, J=9.9 Hz, 1H), 5.12 (dd, J=3.9,5.7 Hz, 1H), 5.05-4.90 (m, 1H), 4.11 (dd, J=3.9, 13.2 Hz, 1H), 4.02-3.88(m, 3H), 2.21-2.06 (m, 1H), 1.49 (ddd, J=2.4, 4.5, 14.1 Hz, 1H), 1.31(d, J=6.9 Hz, 3H).

Example 3j

Under carbon mono-oxide atmosphere, a mixture of 25.0 g of compound 10,11.6 g of i-Pr₂NEt, 12.8 g of 2,4-difluorobenzylamine; 335 mg ofPd(OAc)₂ and 1.9 g of 1,4-bis(diphenylphosphino)butane in 188 mL of DMAwas stirred at 85° C. for 4 h. After cooling, the reaction mixture wasdivided and 10/25 of mixture was used for next step. 6.6 g of AcOEt,29.9 g of water and 3 mg of seed crystal were added to the reactionmixture at 40° C. After stirring for 7 min, 29.9 g of water was addedand cooled to room temperature. The crystal was filtered at roomtemperature and washed by 47.2 g of ethanol to give 10.1 g of compound11 (83% yield) as a crystal.

¹H NMR (300 MHz, CDCl₃) δ 10.40 (t, J=6.0 Hz, 1H), 8.35 (s, 1H),7.66-7.58 (m, 2H), 7.42-7.24 (m, 5H), 6.78-6.74 (m, 2H), 5.30 (d, J=9.9Hz, 1H), 5.26 (d, J=10.2 Hz, 1H), 5.15 (dd, J=3.9, 5.7 Hz, 1H),5.05-4.90 (m, 1H), 4.64 (d, J=5.4 Hz, 2H), 4.22 (dd, J=3.9, 13.5, 1H),4.09 (dd, J=6.0, 13.2 Hz, 1H), 4.02-3.88 (m, 2H), 2.24-1.86 (m, 1H),1.50 (ddd, J=2.4, 4.5, 14.1 Hz, 1H), 1.33 (d, J=7.2 Hz, 3H).

Example 3k

Under hydrogen atmosphere, a mixture of 4.0 g of compound 11 and 0.8 gof 50% wet 5% Pd—C in 67.6 mL of THF and 1.6 mL of H₂O was stirred for1.5 h at 50° C. After mixture of 80 mg of NaHSO₃ and 2.0 mL of purifiedwater was added to the reaction mixture and the reaction mixture wasstirred for 1 h, precipitate was filtered, washed with 20 mL of THF, andthe filtrate was concentrated to 11.97 g. After adding 6.7 mL of ethanoland 33.6 mL of purified water over 1 h, reaction mixture was cooled to25° C. Filtration, washing with 26.9 mL of EtOH and drying provided 2.33g of compound 12 (82% yield) as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 12.51 (s, 1H), 10.36 (t, J=5.7 Hz, 1H), 8.50(s, 1H), 7.39 (td, J=8.7, 6.3 Hz, 1H), 7.24 (ddd, J=2.6, 9.5, 10.8 Hz,1H), 7.12-7.00 (m, 1H), 5.44 (dd, J=3.9, 5.7 Hz, 1H), 4.90-4.70 (m, 1H),4.65-4.50 (m, 1H), 4.54 (d, J=5.1 Hz, 2H), 4.35 (dd, J=6.0, 13.8 Hz,1H), 4.10-3.98 (m, 1H), 3.96-3.86 (m, 1H), 2.10-1.94 (m, 1H), 1.60-1.48(m, 1H), 1.33 (d, J=6.9 Hz, 3H).

Example 3l

After dissolution of 18.0 g of compound 12 (1.0 eq.) in 54 mL of EtOH byheating, followed by filtration, 21.5 mL of 2N NaOHaq. (1.0 eq.) wasadded to the solution at 80° C. The solution was gradually cooled toroom temperature. Filtration, washing with 80 mL of EtOH and dryingprovided 18.8 g of compound 13 (99% yield) as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 10.70 (t, J=6.0 Hz, 1H), 7.89 (s, 1H),7.40-7.30 (m, 1H), 7.25-7.16 (m, 1H), 7.06-6.98 (m, 1H), 5.22-5.12 (m,1H), 4.87-4.74 (m, 1H), 4.51 (d, J=5.4 Hz, 2H), 4.35-4.25 (m, 1H), 4.16(dd, J=1.8, 14.1 Hz, 1H), 4.05-3.90 (m, 1H), 3.86-3.74 (m, 1H),2.00-1.72 (m, 1H), 1.44-1.32 (m, 1H), 1.24 (d, J=6.9 Hz, 3H).

Apparatus and conditions used to generate FIGS. 1-7 are as follows:

Measurement of X-Ray Powder Diffraction Pattern

The measuring conditions used were the same as general metrology for theX-ray powder diffraction pattern measurement described in “The JapanesePharmacopoeia Fifteenth Edition”.

Measuring Apparatus RINT TTR III Methods

The acquisition conditions were as follows.

Measurement Method: parallel beam methodTube anode: Cu

Radiation: Cu Kα

Generator current: 300 mAGenerator tension: 50 kV

The sample was prepared on an aluminum wafer

Angle of incidence: 4° and 40°

Measurement of Infrared Spectroscopy Analysis

The acquisition conditions used for were as follows.

Measuring Apparatus

FT/IR-4200typeA (by JASCO Corporation)

Methods

Measurement method: ATR (Attenuated total reflection) methodResolution: 4 (cm-1)

Detector: DLATGS

Accumulation: 32 times

Measurement of Solid-State ¹³C NMR Spectra

The spectrum was obtained using the cross polarizationmagic-angle-spinning (CP/MAS) method. The acquisition conditions were asfollows.

Measuring Apparatus

Spectrometer: Varian NMR Systems (1H frequency: 599.8 MHz)

Methods Probe: 3.2 mm T3 HX Probe

Spectral width: 43103.4 Hz

Acquisition Time: 0.04 s Recycle Delay: 10 s Contact Time: 3 ms

External standard: adamantane (methyne carbon: 38.52 ppm)

Temperature: 10

MAS rate: 20 kHz

Example A

The starting material of Example A is compound 8, which is identical toformula (Ia). Thus, Example A depicts a process in providing anintermediate for the compound of formula 17 below which is isomeric tothe compound ZZ-2 at page 237 of WO 2006/116764 to Brian Johns et al.

Example Aa

After dissolution of mixture of 320 g of compound 8 (1.0 eq.) in 3.20 Lof MeOH by heating, the solution was concentrated. To the residue, 1.66L of MeCN, 5.72 mL of AcOH (0.1 eq.) and 82.6 g of(S)-2-Amino-propan-1-ol (1.1 eq.) were added and the mixture was heatedto 70° C., stirred at 70° C. for 4 h and concentrated. To the residue,1.67 L of 2-propanol was added and the mixture was concentrated (twice).After cooling of the residue, filtration, washing with 500 mL of cold2-propanol and drying provided 167 g of compound 14 (52% yield) as acrystal.

¹H NMR (300 MHz, CDCl₃) δ 7.61-7.55 (m, 2H), 7.40-7.20 (m, 4H), 6.53 (d,J=7.2, 1 H), 5.46 (d, J=10.5 Hz, 1H), 5.23 (d, J=10.2 Hz, 1H), 5.20 (dd,J=3.9, 9.6 Hz, 1H), 4.46-4.34 (m, 1H), 4.31 (dd, J=6.6, 8.7 Hz, 1H),4.14 (dd, J=3.9, 12.3 Hz, 1H), 3.79 (dd, J=9.9, 12.3 Hz, 1H), 3.62 (dd,J=6.9, 8.7 Hz, 1H), 1.38 (d, J=6.3 Hz, 3H).

Example Ab

To slurry of 156 g of compound 14 (1.0 eq.) in 780 mL of NMP was added93.6 g of NBS (1.1 eq.) and the mixture was stirred at room temperaturefor 2.5 h. The reaction mixture was added to 3.12 L of H₂O. Filtration,washing with 8.0 L of H₂O and drying provided 163 g of compound 15 (84%yield) as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (s, 1H), 7.55-7.50 (m, 2H), 7.42-7.25(m, 3H), 5.34 (dd, J=3.6, 9.9 Hz, 1H), 5.18 (d, J=10.8 Hz, 1H), 5.03 (d,J=10.5 Hz, 1H), 4.53 (dd, J=3.6, 12.0 Hz, 1H), 4.40-4.20 (m, 2H), 3.99(dd, J=9.9, 11.7 Hz, 1H), 3.64 (dd, J=5.7, 8.1 Hz, 1H), 1.27 (d, J=6.3Hz, 3H).

Example Ac

Under carbon mono-oxide atmosphere, a mixture of 163 g of compound 15(1.0 eq.), 163 mL of i-Pr₂NEt (2.5 eq.), 68.4 mL of2,4-difluorobenzylamine (1.5 eq.) and 22.5 g of Pd(PPh₃)₄ (0.05 eq.) in816 mL of DMSO was stirred at 90° C. for 7 h. After cooling, removal ofprecipitate, washing with 50 mL of DMSO and addition of 11.3 g ofPd(PPh₃)₄ (0.025 eq.), the reaction mixture was stirred at 90° C. for 2h under carbon mono-oxide atmosphere again. After cooling, removal ofprecipitate and addition of 2.0 L of AcOEt and 2.0 L of H₂O, the organiclayer was washed with 1.0 L of 1N HClaq. and 1.0 L of H₂O (twice) andthe aqueous layer was extracted with 1.0 L of AcOEt. The organic layerswere combined and concentrated. Silica gel column chromatography of theresidue provided 184 g of compound 16 (96% yield) as foam.

¹H NMR (300 MHz, CDCl₃) δ 10.38 (t, J=6.3 Hz, 1H), 8.39 (s, 1H),7.75-7.25 (m, 7H), 6.90-6.70 (m, 2H), 5.43 (d, J=10.2 Hz, 1H), 5.24 (d,J=10.2 Hz, 1H), 5.19 (dd, J=3.9, 9.9 Hz, 1H), 4.63 (d, J=6.0 Hz, 2H),4.50-4.25 (m, 3H), 3.86 (dd, J=9.9, 12.3 Hz, 1H), 3.66 (dd, J=6.9, 8.4Hz, 1H), 1.39 (d, J=6.0 Hz, 3H).

Example Ad

Under hydrogen atmosphere, a mixture of 184 g of compound 16 (1.0 eq.)and 36.8 g of 10% Pd—C in 3.31 L of THF and 0.37 L of MeOH was stirredfor 3 h. After filtration of precipitate (Pd—C), washing with THF/MeOH(9/1) and addition of 36.8 g of 10% Pd—C, the mixture was stirred for 20min under hydrogen atmosphere. After filtration of precipitate (Pd—C)and washing with THF/MeOH (9/1), the filtrate was concentrated. After200 mL of AcOEt was added to the residue, filtration afforded crudesolid of compound 17. The precipitates were combined and extracted with4.0 L of CHCl₃/MeOH (5/1). After concentration of the CHCl₃/MeOHsolution and addition of 250 mL of AcOEt to the residue, filtrationafforded crude solid of compound 17. The crude solids were combined anddissolved in 8.2 L of MeCN/H₂O (9/1) by heating. After filtration, thefiltrate was concentrated. To the residue, 1.5 L of EtOH was added andthe mixture was concentrated (three times). After cooling of theresidue, filtration and drying provided 132 g of compound 17 (88% yield)as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 11.47 (brs, 1H), 10.31 (t, J=6.0 Hz, 1H),8.46 (s, 1H), 7.40 (td, J=8.6, 6.9 Hz, 1H), 7.24 (ddd, J=2.6, 9.4, 10.6,1H), 7.11-7.01 (m, 1H), 5.39 (dd, J=4.1, 10.4 Hz, 1H), 4.89 (dd, J=4.2,12.3 Hz, 1H), 4.55 (d, J=6.0 Hz, 2H), 4.40 (dd, J=6.8, 8.6 Hz, 1H),4.36-4.22 (m, 1H), 4.00 (dd, J=10.2, 12.3. Hz, 1H), 3.67 (dd, J=6.7, 8.6Hz, 1H), 1.34 (d, J=6.3 Hz, 3H).

Example Ae

After dissolution of 16.0 g of compound 17 (1.0 eq.) in 2.56 L of EtOHand 0.64 L of H₂O by heating, followed by filtration, 39 mL of 1NNaOHaq. (1.0 eq.) was added to the solution at 75° C. The solution wasgradually cooled to room temperature. Filtration, washing with 80 mL ofEtOH and drying provided 13.5 g of compound 18 (80% yield) as a crystal.

¹H NMR (300 MHz, DMSO-d₆) δ 10.73 (t, J=6.0 Hz, 1H), 7.89 (s, 1H),7.40-7.30 (m, 1H), 7.25-7.16 (m, 1H), 7.07-6.98 (m, 1H), 5.21 (dd,J=3.8, 10.0 Hz, 1H), 4.58 (dd, J=3.8, 12.1 Hz, 1H), 4.51 (d, J=5.4 Hz,2H), 4.30-4.20 (m, 2H), 3.75 (dd, J=10.0, 12.1 Hz, 1H), 3.65-3.55 (m,1H), 1.27 (d, J=6.1 Hz, 3H).

Example B

This Example B utilizes a process to insert a ring nitrogen in place ofoxygen in a pyrone ring and create an aldehyde equivalent by an osmiumoxidation of a double bond. Thus, this example is not a bromination ofthe invention.

Example Ba

To a bromobenzene (238 ml) solution of compound A (23.8 g, 110 mmol),selene dioxide (24.4 g, 220 mmol) was added. The reaction mixture wasstirred for 13 hours at 140° C. with removing water by Dean-Stark trap.Insoluble particles were removed by filtration after cooling, andsolvent was evaporated. Toluene was added to the residue andprecipitates were filtered off. After concentration in vaccuo, theresidue was purified by silica gel column chromatography (hexane/ethylacetate). Compound B (16.5 g, 65%) was obtained as yellow oil.

¹H-NMR (CDCl₃) δ: 5.51 (2H, s), 6.50 (1H, d, J=5.4 Hz), 7.36 (5H, s),7.75 (1H, d, J=5.4 Hz), 9.88 (1H, s).

Example Bb

To an ice cooled aqueous (465 ml) solution of sodium chlorite (38.4 g,424 mmol) and sulfamic acid (54.9 g, 566 mmol), acetone (465 ml)solution of compound B (46.5 g, 202 mmol) was added and the mixture wasstirred for 40 minutes at room temperature. After removing acetone invaccuo, precipitates were collected by filtration and washed with coldwater. Compound C (42.8 g, 86%) was obtained as colorless crystal.

¹H-NMR (DMSO-d₆) δ: 5.12 (2H, s), 6.54 (1H, d, J=5.6 Hz), 7.33-7.46 (5H,m), 8.20 (1H, d, J=5.6 Hz).

Example Bc

An ethanol (17 ml) solution of allylamine (13.2 g 231 mmol) was added toan ethanol (69 ml) suspension of compound C (17.2 g, 70 mmol), then themixture was stirred for 4.5 hours at 50° C. and for 3 hours at 75° C. Tothe cooled reaction mixture, 2N hydrochloric acid and ice were added andprecipitates were collected by filtration. Compound D was obtained ascolorless crystal.

¹H-NMR (CDCl₃) δ: 4.37 (2H, brs), 4.95 (2H, s), 5.26-5.39 (2H, m),5.81-5.94 (1H, m), 6.32 (1H, dd, J=0.8, 7.2 Hz), 7.29-7.37 (3H, m),7.48-7.51 (2H, m), 7.99 (1H, dd, J=0.8, 7.6 Hz), 8.11 (1H, brs).

Example Bd

To an acetonitrile (146 ml) suspension of compound D (14.6 g, 51 mmol),1,8-diazabicyco[5.4.0]undec-7-ene (15.5 g, 102 mmol) and methyl iodide(18.2 g, 128 mmol) were added and the mixture was stirred for 15 hoursat room temperature. After evaporating solvent, the residue was purifiedby silica gel column chromatography (chloroform/methanol). Compound E(14.2 g, 93%) was obtained as colorless solid.

¹H-NMR (CDCl₃) δ: 3.75 (3H, s), 4.40 (2H, d, J=5.7 Hz), 5.16-5.35 (2H,m), 5.29 (2H, s), 5.81-5.94 (1H, m), 6.62 (1H, d, J=7.5 Hz), 7.27-7.42(6H, m).

Example Be

To a diethyl ether (390 ml) solution of compound E (13.3 g, 44 mmol),potassium osmate(VI) dihydrate (1.62 g, 4.4 mmol) and sodiummetaperiodate (28.1 g, 132 mmol) were added. The mixture was stirred for2.5 hours at room temperature and precipitates were collected byfiltration. Collected solid was dissolved in chloroform-methanol andinsoluble particles were filtered off. Concentration in vaccuo gavecrude product of compound F (14.3 g). 1H NMR (DMSO-d6) δ: 3.23 (3H, s),3.82 (3H, s), 3.87 (2H, t, J=4.4 Hz), 4.62 (1H, dd, J=11.7, 4.8 Hz),5.11 (2H, s), 6.31 (1H, d, J=7.5 Hz), 6.78 (1H, d, J=6.6 Hz), 7.33-7.40(5H, m), 7.64 (1H, d, J=7.5 Hz).

Example Bf

To chloroform (108 ml) and methanol (12 ml) solution of compound F (11.7g, crude product), 3-aminopropanol (2.77 g, 36.9 mmol), and acetic acid(1.2 ml) were added and the mixture was stirred for 90 minutes at 70° C.After concentrating in vaccuo, the residue was purified by silica gelcolumn chromatography (chloroform/methanol). Compound G (8.48 g, 72% for2 steps) was obtained as colorless crystal.

¹H-NMR (CDCl₃) δ: 1.54-1.64 (1H, m), 1.85-2.01 (1H, m), 3.00 (1H, dt,J=3.6, 12.9 Hz), 3.74 (1H, dt, J=2.7, 12.3 Hz), 3.93 (1H, dd, J=5.1,13.5 Hz), 4.07-4.21 (2H, m), 4.63-4.69 (1H, m), 4.94 (1H, t, J=4.8 Hz),5.25 (2H, dd, J=10.2, 24.6 Hz), 6.56 (1H, d, J=7.5 Hz), 7.22-7.38 (5H,m), 7.63-7.66 (2H, m).

Example Bg

To acetic acid (93 ml) solution of compound G (6.1 g, 18.7 mmol), aceticacid (31 ml) solution of bromine (1.44 ml, 28.0 mmol) was addeddropwisely during 15 minutes. The mixture was stirred for 3 hours atroom temperature. After addition of 5% aqueous sodium hydrogen sulfite(8 ml), 2N sodium hydroxide (500 ml) was added dropwisely during 20minutes. Precipitates were collected by filtration and washed withmixture of dichloromethane and diisopropyl ether. Compound H (6.02 g,79%) was obtained as colorless crystal.

¹H-NMR (DMSO-d₆) δ: 1.55-1.74 (2H, m), 3.12 (1H, dt, J=3.0, 12.3 Hz),3.84 (1H, dt, J=2.7, 11.7 Hz), 4.00-4.05 (1H, m), 4.20-4.26 (1H, m),4.40-4.46 (2H, m), 5.03 (2H, s), 5.15-5.17 (1H, m), 7.31-7.40 (3H, m),7.56-7.58 (2H, m), 8.39 (1H, s).

Example Bh

To dimethyl sulfoxide (1.42 ml) solution of compound H (71 mg, 0.175mmol) and tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.035 mmol),4-fluorobenzyl amine (0.06 ml, 0.525 mmol) and diisopropyl amine (0.15ml, 0.875 mmol) were added, then the mixture was stirred under carbonmonoxide atmosphere for 5 hours at 80° C. After cooling, saturatedaqueous ammonium chloride was added and the mixture was extracted withethyl acetate. The extract was washed with water and dried withanhydrous sodium sulfate. Solvent was removed in vaccuo and the residuewas purified with silica gel column chromatography (ethylacetate/methanol). Compound I (74.5 mg, 89%) was obtained as colorlesscrystal.

¹H-NMR (DMSO-d₆) δ: 1.58-1.74 (2H, m), 3.10-3.18 (1H, m), 3.80-3.88 (1H,m), 4.02-4.07 (1H, m), 4.43-4.59 (5H, m), 5.05 (2H, s), 5.20 (1H, t,J=3.9 Hz), 7.13-7.19 (2H, m), 7.32-7.40 (5H, m), 7.56-7.59 (2H, m), 8.61(1H, s).

Example C Synthesis of methyl5-bromo-1-[2-hydroxy-2-(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate(in equilibrium with the corresponding aldehyde)

This Example C shows a refunctionalization of a compound 6 as shownabove in Example 1 (of formula (VI)), including a bromination at the Feposition, to yield final products 20 and 21 (of formula (I)). Suchcompounds with Br at the Fe position can be reacted as in Examples 1 and2 to add the R²—X—NR′—C(O)— sidechain.

Example Ca Methyl1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate

A reactor was charged with1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylicacid 6 (4.302 kg, 13.47 mol) followed by charging with NaHCO₃ (1.69 kg,20.09 mol) and 242 g of deionized water. To this was added 21.4 kg ofNMP and the mixture was stirred and temperature brought to 28-35° C.Dimethyl sulfate (2.34 kg, 18.30 mol) was added dropwise via an additionfunnel to the reaction mixture over 1-3 hours keeping the temperature at28-33° C. The slurry was agitated at this temperature for 14 h. Whendeemed complete, the reaction mixture was cooled to 5° C. or below andthe mixture was neutralized to pH 6 by the addition of HCl (561 mL ofconc HCl in 2806 g of deionized water). The reaction vessel was slowlycharged with cold 20% brine solution composed of 8.7 kg NaCl, 20 kg ofdeionized water and 14.8 kg of ice at a maximum temperature of 10° C.The mixture was agitated at 0-10° C. for 2.5 h. The slurry was filteredunder vacuum and the cake washed with 15 kg of deionized water twotimes. The wet solid product was dried at 45-55° C. under vacuum untilconstant weight was obtained. The desired product methyl1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate7 was obtained as a light yellow solid (3.77 kg, 99.42% purity by HPLC,84%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.60 (d, J=7.5 Hz, 1H), 7.36 (m, 5H),6.28 (d, J=7.5 Hz, 1H), 5.23 (d, J=5.4 Hz, 1H), 5.10 (Abq, J=10.8 Hz,2H), 4.85 (m, 1H), 3.98 (dd, J=14.3, 2.4 Hz, 1H), 3.79 (s, 3H), 3.70(dd, J=14.3, 9.0 Hz, 1H), 3.58 (m, 1H), 3.23 (m, 1H).

Example Cb Methyl5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate

A reactor was charged with (3.759 kg, 11.27 mol) of methyl1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate7 and 18.8 L of DMF. To this agitated mixture at 18-20° C. was addedN-bromosuccinimide (2.220 kg, 12.47 mol) over 20 minutes via a powderfunnel. The resultant mixture was stirred at rt for 16 h. At this timeless than 1% of starting material was present by HPLC. The mixture wasworked up in half batches by cooling to 10° C. and added an ice/watermixture (12 kg ice in 35 kg deionized water) and the mixture wasagitated, then filtered. This was repeated for the second half of thebatch. The combined filter cake was washed with 14 L of water and driedin a vacuum oven to provide 4.033 kg of methyl5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate19 (91.6%) as an off-white powder of 99.2% HPLC purity. ¹H NMR (300 MHz,Methanol-d₄) δ 8.21 (s, 1H), 7.41-7.33 (m, 5H), 5.16 (s, 2H), 4.17 (dd,J=14.3, 2.4 Hz, 1H), 3.90 (dd, J=14.3, 9.0 Hz, 1H), 3.81 (s, 3H), 3.78(m, 1), 3.52 (dd, J=11.3, 4.8 Hz, 1H), 3.41 (dd, J=11.3, 6.3 Hz, 1H).

Example Cc Methyl5-bromo-1-[2-hydroxy-2-(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate(in equilibrium with the corresponding aldehyde)

A reactor was charged with sodium periodate (1.67 kg, 7.8 mol) and 44 Lof deionized water. To the agitated mixture was added 8.5 kg of ice.This was stirred until all the ice melted and the mixture temperaturewas 1.4° C. To this was added methyl5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate19 (2.73 kg, 6.62 mol) via a powder addition funnel. The mixture wasallowed to warm to rt and the slurry was stirred for 16 h. A sample wasmonitored by ¹H NMR and showed the disappearance of starting material.The mixture was filtered and the cake washed with 20 kg of deionizedwater. This was repeated until a negative starch/iodide paper result wasobtained (4×20 L washes). The solids were dried in a vacuum oven at45-55° C. to provide methyl5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate20 (2.176 kg, 88%) as a mixture with the corresponding aldehyde form 21.Purity was determined to be 99.5% by HPLC. ¹H NMR (300 MHz, acetone-d₆)δ 8.12 (s, 1H), 7.49-7.30 (m, 5H), 5.56 (dd, J=6.0, 2.4 Hz, 1H), 5.23(m, 1H), 5.20 (s, 2H), 3.97 (d, J=5.1 Hz, 2H), 3.87 (s, 3H).

Example 2 Methyl5-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-1-[2-hydroxy-2-(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate(in equilibrium with the corresponding aldehyde)

This Example shows a reaction of a compound 5 of formula (II) with oneof (III) in step i) and a refunctionalization step ii) of compounds offormula (V) (compounds 22, 23, 24 and 25) in producing compounds offormula (I).

Example 2a1-[2,2-Bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylicacid

To a flask (1 L) charged with 500 mL of anhydrous ethanol was added 49.2g (0.2 mol) of 4-oxo-3-[(phenylmethyl)oxy]-4H-pyran-2-carboxylic acid 5.The suspension was slowly heated to 55-60° C. before addition of2-amino-acetaldehyde-dimethylacetal (84.1 g, 0.8 mole). The reaction wasthen brought up to 65° C. and further stirred for 18 hours. The solventwas removed under reduced pressure to produce1-[2,2-Bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylicacid 22 (crude) as brown oil, which was used for the next step directly.

Example 2b Methyl1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate

Crude1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylicacid 22 obtained as above was dissolved in DMF (500 mL). To thissolution was added NaHCO₃(50.5 g, 0.6 mole). The suspension was stirredvigorously with a mechanic stirrer while CH₃I in TBME (2.0 M, 300 mL)was introduced by addition funnel over 30 minutes. After addition, thereaction was stirred overnight at room temperature. The reaction mixturewas then diluted with EtOAc (˜1.5 L) and washed with water and brine.The organic layer was dried over anhydrous Na₂SO₄. Evaporation ofsolvents gave methyl1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate23 as brown oil, which was used directly for the next step.

Example 2c Methyl1-[2,2-bis(methyloxy)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate

A 2 L flask equipped with a mechanic stirrer were charged with methyl1-[2,2-bis(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate23 as obtained above and 500 mL of dichloromethane. To this flask wasadded NBS (30 g, 0.17 mole) portion-wise. The reaction was stirred atroom temperature until its completion (monitored by TLC, ˜6 hours). Themixture was then diluted with dichloromethane and washed with NaHCO₃(ss). The organic phase was dried over Na₂SO₄ before evaporation of thesolvents. The crude product was purified by column chromatography(silica gel, EtOH/DCM: 0-40%) to afford methyl1-[2,2-bis(methyloxy)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate24 as a light brown solid (50 g, 60% over three steps). ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 7.7 (s, 1H), 7.4 (m, 2H), 7.3 (d, J=7.9 Hz, 3H), 5.3(s, 2H), 4.4 (s, 1H), 3.8 (d, J=4.8 Hz, 2H), 3.8 (s, 3H), 3.4 (s, 6H).LC-MS (M+H⁺): calcd 426. obsd 426.

Example 2d Methyl1-[2,2-bis(methyloxy)ethyl]-5-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate

A pressure vessel was charged with methyl1-[2,2-bis(methyloxy)ethyl]-5-bromo-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate24 (6.4 g, 15 mmol), 2,4-difluorobenzylamine (3.2 g, 22.5 mmol), K₃PO₄(9.45 g, 45 mmol), Pd(OCOCF₃)₂ (398 mg, 1.2 mmol), Xantophos (694 mg,1.2 mmol) and toluene (200 mL). The mixture was purged by CO (4×) beforebeing heated to 100° C. for 22 hours under CO atmosphere (60 psi). Aftercooled down to the room temperature, the solids were filtered offthrough celite and washed with EtOAc. The filtrate was concentrated andthe residual was purified by column chromatography (silica gel,EtOAc/hexane 0-80%) to afford methyl1-[2,2-bis(methyloxy)ethyl]-5-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate25 as a light brown oil (4.7 g, 61%).

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.4 (m, 1H), 8.4 (s, 1H), 7.4 (m,6H), 6.8 (d, J=9.3 Hz, 2H), 5.3 (s, 2H), 4.6 (d, J=5.7 Hz, 2H), 4.5 (s,1H), 4.0 (d, J=4.8 Hz, 2H), 3.8 (s, 3H), 3.4 (s, 6H). LC-MS (M+H⁺):calcd 517. obsd 517.

Example 2e Methyl5-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-1-[2-hydroxy-2-(methyloxy)ethyl]-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate(in equilibrium with the corresponding aldehyde)

Methyl1-[2,2-bis(methyloxy)ethyl]-5-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate25 (11.6 g) was treated with 90% formic acid (250 mL) at 40° C. for ˜12hours (monitored by LC-MS). After the solvents were evaporated at <40°C., the residue was re-dissolved in EtOAc (˜1 L) and the resultingsolution was washed with NaHCO₃ and brine. The organic phase was thendried over Na2SO₄. After evaporation of solvents, the titled compounds26 and 27 were obtained as an approximate 80/20 equilibrium mixture(10.57 g). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.3 (m, 1H), 9.47 (s,aldehyde-H. ˜0.2H)), 8.4 (m, 1H), 7.3 (s, 6H), 7.2 (m, 1H), 7.0 (m, 1H),6.3 (m, 2H), 5.1 (s, 3H), 4.9 (m, 1H), 4.5 (m, 3H), 3.9 (m, 2H), 3.8 (s,3H). LC-MS, for 26 (M+H⁺), calcd 503. obsd 503. for 27 (M+H₂O+H⁺), calcd489, obsd 489.

Example CC(4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide

Example CCa(4aS,13aR)-8-Bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-9,11-dione(DD)

A reactor was charged with [(2R)-2-pyrrolidinylmethyl]amine (0.75 kg)and 4.6 L of DMF was added followed by 0.45 kg of glacial acetic acid.Acetonitrile (41.4 L) was then added and the mixture was agitated for 15minutes. To the reaction mixture was added methyl5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate(2.30 kg). After stirring for 20 minutes at ambient temperature, themixture was heated at 75-85° C. until the bromide starting material wasconsumed by HPLC analysis (about 6 hrs). Upon completion, the mixturewas cooled until the reflux subsided and then charged with 6.9 L ofmethanol and the mixture was heated at reflux for about 45 minutes thencooled to 15° C. and filtered and dried to provide(4aS,13aR)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-9,11-dione(1.93 kg, 78%) as a white solid). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.65(m, 1H), 7.54 (m, 2H), 7.33 (m, 3H), 5.15 (d, 1H), 4.99 (d, 1H), 4.60(m, 1H), 4.36 (m, 1H), 4.03 (m, 1H), 3.90 (m, 1H), 3.65 (m, 1H),3.06-2.84 (m, 3H), 1.92-1.60 (m, 4H).

Example CCb(4aS,13)-N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide

A reaction vessel was charged with(4aS,13aR)-8-bromo-10-[(phenylmethyl)oxy]-2,3,4a,5,13,13a-hexahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-9,11-dione(1.4 kg), 2,4-difluorobenzylamine (705 g), Hunigs base (1.4 L), dppf (60g) and DMSO (12 L). The mixture was degassed with high purity nitrogen 4times. To this mixture was added palladium (II) trifluoroacetate (18 g)in DMSO (2 L). The mixture was again degassed 3 times with high puritynitrogen and then purged with CO 3 times and left under a 45 psiatmosphere of CO. The mixture was heated at 80° C. under 45 psi CO untilthe reaction appeared complete by HPLC (24 hrs). The mixture was cooledto rt and slowly transferred to an ice slurry of ammonium chloride. Themixture was filtered and washed with water and isopropanol. The residuewas recrystallized from isopropanol to provide(4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide(952 g, 56%). Recrystallization of the mother liquor from isopropanolproduced a second crop of crystals of the desired product in the amountof 327 g (19%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.44 (m, 1H), 8.55 (s,1H), 7.56-7.07 (m, 8H), 5.18 (d, 1H), 5.03 (d, 1H), 4.62-4.54 (m, 4H),4.06-3.60 (m, 3H), 3.20-2.80 (m, 3H), 1.93-1.60 (m, 4H).

Example CCc(4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide

A pressure reaction vessel was charged with(4aS,13aR)—N-[(2,4-Difluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide(950 g), 192 g of palladium on carbon (50% wet), ethanol (9.5 L) andconcentrated ammonium hydroxide (124 mL). The mixture was degassed withnitrogen 3 times and then placed under 50 psi of hydrogen until thereaction was complete. The mixture was degassed again with nitrogen andthen filtered through Celite. The cake was extracted with refluxingdichloromethane and then filtered again. The combined filtrates wereconcentrated to a small volume (4 L), azeotroped with ethanol (28.5 L)to a final volume of 9 L. The slurry was filtered and washed withethanol and dried to produce(4aS,13aR)—N-[(2,4-difluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide(616 g, 78.4%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.37(m, 1H), 8.42 (s, 1H), 7.41-7.05 (m, 3H), 4.72-4.53 (m, 4H), 4.05 (m,1H), 3.86 (m, 1H), 3.70 (m, 1H), 3.16 (m, 1H), 2.88 (m, 2H), 1.92-1.60(m, 4H).

1-29. (canceled)
 30. A process for the preparation of a compound of thefollowing formula (I):

wherein R is —CHO, —CH(OH)₂ or —CH(OH)(OR⁴); P¹ is H or a hydroxylprotecting group; P³ is H or a carboxy protecting group; R³ is H,halogen, hydroxy, optionally substituted lower alkyl, optionallysubstituted cycloalkyl, optionally substituted lower alkenyl, optionallysubstituted lower alkoxy, optionally substituted lower alkenyloxy,optionally substituted aryl, optionally substituted aryloxy, optionallysubstituted heterocyclic group, optionally substituted heterocycleoxyand optionally substituted amino; R⁴ is lower alkyl; R^(x) is H, halogenor R²—X—NR¹—C(O)—; R² is optionally substituted aryl; X is a singlebond, a heteroatom group selected from the group consisting of O, S, SO,SO₂, and NH or a lower alkylene or a lower alkenylene wherein each maybe intervened by the heteroatom; and R¹ is H or lower alkyl, whichcomprises the steps of: i) reacting a compound of formula (II):

wherein P¹, P³, R^(x) and R³ are defined above; with an amine of formula(III) or (IV):

wherein R⁵ and R⁶ are independently lower alkyl or R⁵ and R⁶ can bealkyl and joined to form a 5-, 6-, or 7-membered ring, to produce anintermediate of formula (V) or (VI), respectively:

wherein P¹, P³, R^(x), R³, R⁵ and R⁶ are defined above; and ii)refunctionalizing the intermediate of formula (V) or (VI) to produce thecompound of formula (I).
 31. The process according to claim 30, whereinin the compound of formula (I), R^(x) is H or Br.
 32. The processaccording to claim 30, wherein in the compound of formula (I), P¹ is Hor Bn.
 33. The process according to claim 30, wherein in the compound offormula (I), R³ is H.
 34. The process according to claim 30, wherein inthe compound of formula (I), P³ is H or Me.
 35. The process according toclaim 30, wherein the compound of formula (II) is


36. The process according to claim 30, wherein the compound of formula(VI) is


37. The process according to claim 30, wherein the compound of formula(VI) is


38. The process according to claim 30, wherein the compound of formula(I) is


39. The process according to claim 30, wherein the amine isH₂NCH₂CH₂CH₂OH.
 40. The process according to claim 30, wherein R^(x) isp-F-phenyl-CH₂—NH—C(O)—, R³ is H, P¹ is Bn and P³ is a carboxyprotecting group.
 41. The process according to claim 30, wherein step i)is carried out in EtOH, THF or DMF at a temperature of about 50-150° C.42. The process according to claim 30, wherein step ii) is carried outusing the intermediate of formula (VI) with an oxidizing agent selectedfrom the group consisting of NaIO₄, RuO₄ and Pb(OAc)₄ in a solventselected from the group consisting of H₂O, MeOH and CH₃CN.
 43. Theprocess according to claim 30, wherein step ii) is carried out using theintermediate of formula (V) with an acid selected from the groupconsisting of HCl, CF₃COOH and HCOH.
 44. The process according to claim30, wherein step ii) includes refunctionalization of R^(x) from R^(x)=Hto R^(x)=Br.
 45. The process according to claim 30, wherein step ii)includes refunctionalization of R^(x) to R^(x)=R²—X—NR¹—C(O)—.
 46. Theprocess according to claim 30, wherein step ii) includesrefunctionalization of P³ from P³=H to P³=Me.